US5945124A - Oral pharmaceutical composition with delayed release of active ingredient for pantoprazole - Google Patents

Oral pharmaceutical composition with delayed release of active ingredient for pantoprazole Download PDF

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Publication number
US5945124A
US5945124A US08/498,386 US49838695A US5945124A US 5945124 A US5945124 A US 5945124A US 49838695 A US49838695 A US 49838695A US 5945124 A US5945124 A US 5945124A
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Prior art keywords
pantoprazole
release
oral pharmaceutical
pharmaceutical composition
active ingredient
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US08/498,386
Inventor
George Sachs
Rango Dietrich
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Takeda GmbH
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Byk Gulden Lomberg Chemische Fabrik GmbH
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Priority to US08/498,386 priority Critical patent/US5945124A/en
Assigned to BYK GULDEN CHEMISCHE FABRIK GMBH reassignment BYK GULDEN CHEMISCHE FABRIK GMBH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DIETRICH, RANGO, SACHS, GEORGE
Priority to AU65174/96A priority patent/AU6517496A/en
Priority to CA002587000A priority patent/CA2587000A1/en
Priority to AT96924849T priority patent/ATE232090T1/en
Priority to DE69636104T priority patent/DE69636104T2/en
Priority to EP02005081A priority patent/EP1213015B1/en
Priority to CA002232450A priority patent/CA2232450C/en
Priority to DE69626116T priority patent/DE69626116T2/en
Priority to ES02005081T priority patent/ES2263700T3/en
Priority to HK98112159.5A priority patent/HK1010836B/en
Priority to SI9630595T priority patent/SI0841903T1/en
Priority to PT96924849T priority patent/PT841903E/en
Priority to DK02005081T priority patent/DK1213015T3/en
Priority to ES96924849T priority patent/ES2192226T3/en
Priority to PCT/EP1996/002892 priority patent/WO1997002020A1/en
Priority to AT02005081T priority patent/ATE324872T1/en
Priority to EP96924849A priority patent/EP0841903B1/en
Priority to JP9504811A priority patent/JPH11508577A/en
Priority to DK96924849T priority patent/DK0841903T3/en
Priority to PT02005081T priority patent/PT1213015E/en
Priority to US09/042,090 priority patent/US6068856A/en
Publication of US5945124A publication Critical patent/US5945124A/en
Application granted granted Critical
Priority to US09/461,388 priority patent/US6274173B1/en
Assigned to ALTANA PHARMA AG reassignment ALTANA PHARMA AG CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: BYK GULDEN LOMBERG CHEMISCHE FABRIK GMBH
Priority to CY0400047A priority patent/CY2459B1/en
Assigned to NYCOMED GMBH reassignment NYCOMED GMBH CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: ALTANA PHARMA AG
Assigned to TAKEDA GMBH reassignment TAKEDA GMBH CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: NYCOMED GMBH
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to oral pharmaceutical compositions in pellet or tablet form for combined use of pantoprazole with an antimicrobially-active ingredient for the treatment of disorders caused by Helicobacter.
  • Pyridin-2-ylmethylsulfinyl-lH-benzimidazoles as disclosed, for example, in EP-A 0005129, EP-A 0166287 and EP-A 0268956 are becoming increasingly important, because of their H + /K + ATPase-inhibiting action, for the therapy of diseases which originate from increased gastric acid secretion.
  • active ingredients which are already commercially available from this group are omeprazole (INN), lansoprazole (INN) and pantoprazole (INN). These active ingredients are also called irreversible proton pump inhibitors.
  • EP-A 0519365 proposes (for the active ingredient pantoprazole) a formulation based on the principle of an alkaline core coated with a water-soluble intermediate layer and with an enteric layer, where improved stability is achieved by using polyvinylpyrrolidone and/or hydroxypropylmethylcellulose as binder for the alkaline core.
  • EP-A 0342522 discloses a formulation for acid-sensitive benzimidazoles, in which an intermediate layer is located between the alkaline core and the enteric coating and is composed of a film-forming material which has only low solubility in water, such as ethylcellulose and polyvinyl acetate, and of a fine-particle inorganic or organic material which is suspended therein and has low solubility in water, such as magnesium oxide, silicon oxide or sucrose fatty acid esters.
  • JP-A 59020219 discloses an enteric composition for acid-labile active ingredients which comprises (under the enteric coating) an intermediate layer of a film-forming material, such as hydroxypropylmethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose phthalate with a content of higher fatty acids.
  • a film-forming material such as hydroxypropylmethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose phthalate with a content of higher fatty acids.
  • DE-A 3233764 proposes for enteric compositions an intermediate layer which is formed from a water-soluble cellulose ether and a water-soluble mono- or polybasic organic acid, such as citric acid, tartaric acid, and the like.
  • pantoprazole in slow-release dosage form (extended release form). It must be regarded as particularly surprising that, in addition, administration of the slow-release pantoprazole results in the onset of action taking place significantly faster than on administration in a form without retarding such release. The duration of treatment until Helicobacter is eradicated is shortened, saving considerable amounts of antibiotic and acid inhibitor.
  • the invention thus relates to oral pharmaceutical compositions in pellet or tablet form for combined use of pantoprazole with an antimicrobially-active ingredient for treatment of disorders caused by Helicobacter, wherein pantoprazole is present at least partly in slow-release form.
  • pantoprazole is the compound, 5-difluoromethoxy-2- (3,4-dimethoxy-2-pyridinyl)methylsulfinyl!-lH-benzimidazole, its salts and solvates (e.g. hydrates), in particular the sodium salt with one and a half molecules of water of crystallization (pantoprazole Na ⁇ 1.5 H 2 O).
  • suitable antimicrobially-active ingredients active against Helicobacter and, in particular, against Helicobacter pylori
  • active ingredients include, for example, bismuth salts (such as bismuth subcitrate or bismuth subsalicylate), sulfonamides, nitrofurans (such as nitrofurazone, nitrofurantoin or furazolidone), metronidazole, tinidazole, nimorazole or antibiotics.
  • antibiotics which may be mentioned in this connection are, arranged according to particular classes of active ingredient: aminoglycosides, such as gentamicin, neomycin, kanamycin, amikacin or streptomycin; macrolides, such as erythromycin, azithromycin, clarithromycin, clindamycin or rifampicin; penicillins, such as penicillin G, penicillin V, ampicillin, mezlocillin or amoxicillin; polypeptides, such as bacitracin or polymyxin; tetracylines, such as tetracyline, chlorotetracycline, oxytetracycline, minocycline or doxycycline; carbapenems, such as imipenem, loracarbef, meropenem or panipenem; cephalosporins, such as cefalexin, cefoxitin, cefuroxime axetil, cefotaxime, cefpodoxim proxet
  • pantoprazole with a plurality of antimicrobially-active ingredients, for example with a combination of bismuth salt and/or tetracycline with metronidazole, or with the combination of amoxicillin or clarithromycin with metronidazole.
  • Antimicrobially-active ingredients which may be emphasized are erythromycin, azithromycin, clarithromycin, clindamycin, rifampicin, ampicillin, mezlocillin, amoxicillin, tetracycline, minocycline, doxycycline, imipenem, meropenem, cefalexin, cefuroxime axetil, cefpodoxime proxetil, cefaclor, cefadroxil, ciprofloxacin, norfloxacin, ofloxacin and pefloxacin.
  • Clarithromycin and amoxicillin may be mentioned as antimicrobially-active ingredients which should be particularly emphasized.
  • Combined administration means for the purpose of the present invention, fixed and, in particular, free combinations, i.e. either slow-release pantoprazole and the antimicrobially-active ingredient are present together in one dosage unit, or slow-release pantoprazole and antimicrobially-active ingredient, which are present in separate dosage units, are administered in direct succession or at a relatively large time interval; a relatively large time interval means a time span up to a maximum of 24 hours. For use as separate dosage units, these are preferably made available together in one pack.
  • the two dosage units are packed together in blister packs which are designed with regard to the relative arrangement of the two dosage units with respect to one another, the inscription and/or coloring in a manner known per se so that the times for taking the individual components (dosage regimen) of the two dosage units are evident to a patient.
  • a dosage unit means, in particular, a medicinal dosage form in which slowing of pantoprazole release is achieved with as few problems as possible.
  • This includes, in particular, tablets, coated tablets or pellets, and microtablets in capsules, with the dosage form advantageously being designed so that the two active-ingredient components (pantoprazole on the one hand and antimicrobially-active ingredient on the other hand) are released, or made available effectively for the body, in such as way that an optimal active ingredient profile, and thus action profile, is achieved.
  • pantoprazole plasma level which persists as long as possible and is sufficient for raising pH, is ensured.
  • the pharmaceutical formulation of the antimicrobially-active ingredient is carried out as is familiar per se to the skilled worker for the individual active ingredient.
  • Rapid release of part of the pantoprazole and extending release of another part can be achieved, for example, also by layered tablets or multilayer tablets, in which case part of the pantoprazole is present in an outer coating in a form without retarding its release; this is followed by another coating containing the antimicrobially-active ingredient and then the core with the pantoprazole, whose release is extended in a suitable manner.
  • the dosage of the active ingredients depends greatly on the nature of the antimicrobially-active ingredients used.
  • a typical dosage for pantoprazole can be regarded as being a daily dose of from about 0.01 to about 20, preferably from 0.05 to 5, in particular from 0.1 to 1.5, mg/kg of body weight, where appropriate in the form of a plurality of single doses.
  • Penicillins, such as amoxicillin, are administered in a daily dose of from about 5 to 40, preferably from 10 to 20, mg/kg of body weight.
  • pantoprazole Because of a great tendency to decompose in a neutral and, in particular, acidic environment, which also results in highly colored decomposition products, for oral compositions, it is necessary on the one hand to keep pantoprazole in an alkaline environment and, on the other hand, to protect it from exposure to acids. It is generally known to coat tablets or pellets which contain an acid-labile active ingredient with an enteric coating which, after passage through the stomach, rapidly dissolves in the alkaline medium in the intestine. In the case of pantoprazole, which in very acid-labile, it is necessary to process it in the tablet core or in pellets in the form of its alkaline salts, for example as sodium salts, or together with alkaline substances.
  • EP-A 0244380 proposes to coat cores which contain the active ingredient together with alkaline compounds or as alkaline salt with at least one layer, which is soluble in water or rapidly disintegrates in water, of nonacidic, inert pharmaceutically-acceptable substance before the enteric layer is applied.
  • the intermediate layer or intermediate layers act as pH-buffering zones in which hydrogen ions, which diffuse in from the outside, are able to react with the hydroxyl ions which diffuse out of the alkaline core.
  • buffer substance In order to increase the buffer capacity of the intermediate layer, it is proposed to incorporate buffer substance into the intermediate layer(s). It is possible in practice by this method to obtain rather stable compositions. However, relatively thick intermediate layers are required to prevent the unsightly discoloration which occurs even on only slight decomposition. In addition, considerable effort must be made to avoid traces of moisture during manufacture.
  • This aim is particularly advantageously achieved by providing at least one release-slowing intermediate layer of water-insoluble film former, which at the same time represents a barrier for mutual interactions between the active ingredient with an alkaline reaction and the enteric coating with an acidic reaction.
  • film formers are regarded as insoluble in water when they cannot be dissolved in water without further additions (organic solvents, detergents, alkalizing substances, etc.).
  • the invention therefore also relates to an oral pharmaceutical composition in pellet or tablet form for acid-labile irreversible proton pump inhibitors comprising an alkaline pellet or tablet core, at least one release-slowing, release-controlling intermediate layer and an outer enteric layer which is soluble in the small intestine, wherein the intermediate layer for the pharmaceutical composition is formed from a water-insoluble film former, the film former being applied from anhydrous solution or aqueous dispersion.
  • the slowing of release can be achieved, for example, by a semipermeable membrane, as disclosed in numerous patents (e.g. EP B 0185331).
  • the oral pharmaceutical compositions according to the invention are distinguished from the prior art by controlled release of active ingredients and increased stability. It is particularly advantageous to keep the intermediate layer (which controls the release of active ingredients) very thin (between 20 and 80, preferably between 40 and 60, ⁇ m), which leads to a considerable saving of material and shorter processing times.
  • the insolubility of the intermediate layer in water means that the application of the enteric layer in the form of aqueous suspensions is not critical because there can be no dissolution of the intermediate layer.
  • oral pharmaceutical compositions with a considerably smoother surface are obtained, which not only leads to a better visual appearance but also technically simplifies an imprinting process for tablets.
  • a suitable binder is, in particular, polyvinylpyrrolidone in various degrees of polymerization.
  • lubricants and nonstick agents which may be mentioned are higher fatty acids and their alkali-metal and alkaline-earth-metal salts, such as calcium stearate.
  • Suitable tablet disintegrants are, in particular, chemically inert agents. Tablet disintegrants which may be mentioned as preferred are crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcelluloses and sodium starch glycolate.
  • Examples of film-forming polymers which can be used in the water-insoluble release-slowing intermediate layer(s) (to be applied to the pellet or tablet core) include ethylcellulose, polyvinyl acetate, Eudragit® RS, Eudragit® RL, etc. (Each of Eudragit® RS and Eudragit® RL is an ammonio methacrylate copolymer.)
  • the release rate can be controlled not only by incorporating therein suitable water-soluble pore formers, such as PEG, lactose, mannitol, sorbitol, HPMC, etc., but also by the thickness of the coating layer applied.
  • the solvents or dispersants used for the release-controlling polymer dispersion are non-aqueous organic solvents, such as alcohols, ketones or halogenated hydrocarbons or mixtures of such solvents.
  • Suitable polymers for the enteric coating are methacrylic acid/methyl methacrylate copolymer or methacrylic acid/ethyl methacrylate copolymer (Eudragit® L) or cellulose derivatives, such as carboxymethylethylcellulose (CMEC, Duodcel), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HP50, HPSS), hydroxypropylmethylcellulose acetate succinate (HPMCAS) or polyvinyl acetate phthalate, to which it is also possible to add, if desired, plasticizer (such as propylene glycol) and/or other additives and ancillary substances (e.g. buffers, bases, such as, preferably, aluminum hydroxide, or pigments).
  • plasticizer such as propylene glycol
  • ancillary substances e.g. buffers, bases, such as, preferably, aluminum hydroxide, or pigments.
  • the layers are applied in conventional ways using equipment customary for these purposes.
  • a) is mixed with one part of b), c) and d).
  • the remainder of b) and c) is added to the clear aqueous solution of e), and the pH is adjusted to > 10 with b).
  • This solution is used for fluidized bed granulation.
  • the remainder of d) and f) is added to the dried granules, and the granules are compressed in a suitable tabletting machine.
  • solution (A) is dissolved in 165 ml of isopropanol to prepare solution (A).
  • a fine suspension of h) in 165 ml of isopropanol is prepared using a rotor-stator agitator, and subsequently i) and j) are stirred in using a suitable agitator to prepare suspension
  • the solution (A) and the suspension (B) are combined.
  • the tablet cores obtained from I are coated to an adequate layer thickness with the suspension obtained above in suitable apparatus.
  • a fine dispersion of h) in 150 ml of a 1:1 acetone/choroform mixture is prepared using a rotor-stator agitator, and subsequently i) and j) are stirred in using a suitable agitator to prepare a suspension (B).
  • Solution (A) and suspension (B) are combined.
  • the tablet cores obtained in I are coated to a sufficient layer thickness with the suspension obtained above in suitable apparatus.
  • the dispersion from III is sprayed onto the presealed cores obtained in II in suitable equipment.
  • a) is sprayed with an aqueous solution of b), c) and d) in a fluidized bed (Wurster method).
  • a release-slowing layer is applied in analogy to the procedure described for tablets in a pan or fluidized bed.
  • the coating is applied in analogy to the procedure described for the tablets in a pan or fluidized bed.
  • pellets are subsequently packed into capsules of suitable size (e.g. size 1).
  • c)-f) are premixed dry and subsequently moistened to a paste-like consistency with a solution of Na carbonate and Na carboxymethylcellulose in water in a conventional kneader or high-speed mixer.
  • the resulting composition is then extruded and shaped into pellets by the extruder/rounder method familiar to the skilled worker.
  • the moistened pellets are dried in suitable equipment (drying oven, fluidized bed, etc.).
  • the release-slowing layer is applied in analogy to the procedure described for tablets in a pan or fluidized bed.
  • the coating is applied in analogy to the procedure described for tablets in a pan or fluidized bed.
  • pellets are subsequently packed into capsules of suitable size (e.g. size 1).

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Abstract

An oral pharmaceutical composition of pantoprazole in pellet or tablet form, wherein the pantoprazole is at least partly in slow-release form, is distinguished, on combined administration with an antimicrobially-active ingredient, by an enhanced action of rapid onset against disorders caused by Helicobacter.

Description

RELATED APPLICATION
This application is related to Applicants' concurrently-filed application Ser. No. 08/498,391.
FIELD OF THE INVENTION
The present invention relates to oral pharmaceutical compositions in pellet or tablet form for combined use of pantoprazole with an antimicrobially-active ingredient for the treatment of disorders caused by Helicobacter.
BACKGROUND
Pyridin-2-ylmethylsulfinyl-lH-benzimidazoles, as disclosed, for example, in EP-A 0005129, EP-A 0166287 and EP-A 0268956 are becoming increasingly important, because of their H+ /K+ ATPase-inhibiting action, for the therapy of diseases which originate from increased gastric acid secretion. Examples of active ingredients which are already commercially available from this group are omeprazole (INN), lansoprazole (INN) and pantoprazole (INN). These active ingredients are also called irreversible proton pump inhibitors.
Control of the microbe, Helicobacter pylori, which is thought to be responsible for certain gastric disorders, by combined use of an antimicrobially-active ingredient which is active against Helicobacter pylori and of an agent which reduces gastric acid has been regarded as the method of choice for some time.
EP-A 0519365 proposes (for the active ingredient pantoprazole) a formulation based on the principle of an alkaline core coated with a water-soluble intermediate layer and with an enteric layer, where improved stability is achieved by using polyvinylpyrrolidone and/or hydroxypropylmethylcellulose as binder for the alkaline core.
EP-A 0342522 discloses a formulation for acid-sensitive benzimidazoles, in which an intermediate layer is located between the alkaline core and the enteric coating and is composed of a film-forming material which has only low solubility in water, such as ethylcellulose and polyvinyl acetate, and of a fine-particle inorganic or organic material which is suspended therein and has low solubility in water, such as magnesium oxide, silicon oxide or sucrose fatty acid esters.
JP-A 59020219 discloses an enteric composition for acid-labile active ingredients which comprises (under the enteric coating) an intermediate layer of a film-forming material, such as hydroxypropylmethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose phthalate with a content of higher fatty acids.
DE-A 3233764 proposes for enteric compositions an intermediate layer which is formed from a water-soluble cellulose ether and a water-soluble mono- or polybasic organic acid, such as citric acid, tartaric acid, and the like.
Combined use of irreversible proton pump inhibitors with antimicrobially-active ingredients does indeed show a good effect against Helicobacter in vitro. However, the clinical effect achieved with this combined use is disappointing. Of practical inconvenience is the great delay in the onset of action.
SUMMARY OF THE INVENTION
The action of an antimicrobially-active ingredient on Helicobacter surprisingly is enhanced by administering pantoprazole in slow-release dosage form (extended release form). It must be regarded as particularly surprising that, in addition, administration of the slow-release pantoprazole results in the onset of action taking place significantly faster than on administration in a form without retarding such release. The duration of treatment until Helicobacter is eradicated is shortened, saving considerable amounts of antibiotic and acid inhibitor.
The invention thus relates to oral pharmaceutical compositions in pellet or tablet form for combined use of pantoprazole with an antimicrobially-active ingredient for treatment of disorders caused by Helicobacter, wherein pantoprazole is present at least partly in slow-release form.
DETAILS
In connection with the present invention, pantoprazole is the compound, 5-difluoromethoxy-2- (3,4-dimethoxy-2-pyridinyl)methylsulfinyl!-lH-benzimidazole, its salts and solvates (e.g. hydrates), in particular the sodium salt with one and a half molecules of water of crystallization (pantoprazole Na×1.5 H2 O).
Examples of suitable antimicrobially-active ingredients (active against Helicobacter and, in particular, against Helicobacter pylori) are enumerated in European Patent Application EP-A 0282131. These active ingredients include, for example, bismuth salts (such as bismuth subcitrate or bismuth subsalicylate), sulfonamides, nitrofurans (such as nitrofurazone, nitrofurantoin or furazolidone), metronidazole, tinidazole, nimorazole or antibiotics. Examples of antibiotics which may be mentioned in this connection are, arranged according to particular classes of active ingredient: aminoglycosides, such as gentamicin, neomycin, kanamycin, amikacin or streptomycin; macrolides, such as erythromycin, azithromycin, clarithromycin, clindamycin or rifampicin; penicillins, such as penicillin G, penicillin V, ampicillin, mezlocillin or amoxicillin; polypeptides, such as bacitracin or polymyxin; tetracylines, such as tetracyline, chlorotetracycline, oxytetracycline, minocycline or doxycycline; carbapenems, such as imipenem, loracarbef, meropenem or panipenem; cephalosporins, such as cefalexin, cefoxitin, cefuroxime axetil, cefotaxime, cefpodoxim proxetil, cefaclor, cefadroxil or cephalothin; gyrase inhibitors, such as ciprofloxacin, norfloxacin, ofloxacin or pefloxacin, or other different antibiotics, such as chloramphenicol.
Particularly worthy of mention in this connection is also the conjoint administration of pantoprazole with a plurality of antimicrobially-active ingredients, for example with a combination of bismuth salt and/or tetracycline with metronidazole, or with the combination of amoxicillin or clarithromycin with metronidazole.
Antimicrobially-active ingredients which may be emphasized are erythromycin, azithromycin, clarithromycin, clindamycin, rifampicin, ampicillin, mezlocillin, amoxicillin, tetracycline, minocycline, doxycycline, imipenem, meropenem, cefalexin, cefuroxime axetil, cefpodoxime proxetil, cefaclor, cefadroxil, ciprofloxacin, norfloxacin, ofloxacin and pefloxacin.
Clarithromycin and amoxicillin may be mentioned as antimicrobially-active ingredients which should be particularly emphasized.
Combined administration means, for the purpose of the present invention, fixed and, in particular, free combinations, i.e. either slow-release pantoprazole and the antimicrobially-active ingredient are present together in one dosage unit, or slow-release pantoprazole and antimicrobially-active ingredient, which are present in separate dosage units, are administered in direct succession or at a relatively large time interval; a relatively large time interval means a time span up to a maximum of 24 hours. For use as separate dosage units, these are preferably made available together in one pack. For example, the two dosage units are packed together in blister packs which are designed with regard to the relative arrangement of the two dosage units with respect to one another, the inscription and/or coloring in a manner known per se so that the times for taking the individual components (dosage regimen) of the two dosage units are evident to a patient.
A dosage unit means, in particular, a medicinal dosage form in which slowing of pantoprazole release is achieved with as few problems as possible. This includes, in particular, tablets, coated tablets or pellets, and microtablets in capsules, with the dosage form advantageously being designed so that the two active-ingredient components (pantoprazole on the one hand and antimicrobially-active ingredient on the other hand) are released, or made available effectively for the body, in such as way that an optimal active ingredient profile, and thus action profile, is achieved.
It is possible to use (for retarding release) various types and degrees of retardation so that a pantoprazole plasma level, which persists as long as possible and is sufficient for raising pH, is ensured.
The pharmaceutical formulation of the antimicrobially-active ingredient is carried out as is familiar per se to the skilled worker for the individual active ingredient.
Rapid release of part of the pantoprazole and extending release of another part can be achieved, for example, also by layered tablets or multilayer tablets, in which case part of the pantoprazole is present in an outer coating in a form without retarding its release; this is followed by another coating containing the antimicrobially-active ingredient and then the core with the pantoprazole, whose release is extended in a suitable manner.
The details of how to achieve slowing of or extending release are familiar to the skilled worker on the basis of his expert knowledge. The skilled worker is likewise familiar with suitable ancillary substances and vehicles for the required dosage forms (pharmaceutical formulations). Besides solvents, tablet auxiliary substances and other active ingredient excipients it is possible to use, for example, tablet-coating compositions, plasticizers, antioxidants, preservatives, dyes, etc. Where incompatibilities between the active ingredients or between the active ingredients and ancillary substances are expected, suitable separating layers are provided where appropriate (for example in layered or multi-layer tablets).
The dosage of the active ingredients depends greatly on the nature of the antimicrobially-active ingredients used. A typical dosage for pantoprazole can be regarded as being a daily dose of from about 0.01 to about 20, preferably from 0.05 to 5, in particular from 0.1 to 1.5, mg/kg of body weight, where appropriate in the form of a plurality of single doses. Penicillins, such as amoxicillin, are administered in a daily dose of from about 5 to 40, preferably from 10 to 20, mg/kg of body weight.
Because of a great tendency to decompose in a neutral and, in particular, acidic environment, which also results in highly colored decomposition products, for oral compositions, it is necessary on the one hand to keep pantoprazole in an alkaline environment and, on the other hand, to protect it from exposure to acids. It is generally known to coat tablets or pellets which contain an acid-labile active ingredient with an enteric coating which, after passage through the stomach, rapidly dissolves in the alkaline medium in the intestine. In the case of pantoprazole, which in very acid-labile, it is necessary to process it in the tablet core or in pellets in the form of its alkaline salts, for example as sodium salts, or together with alkaline substances. Since the substances suitable for enteric coatings contain free carboxyl groups, a problem arises when the enteric coating is partly or even completely dissolved from the inside because of the alkaline medium in the interior, and the free carboxyl groups promote decomposition of the active ingredients. It is therefore necessary to provide a sealing intermediate layer (subcoating) between the enteric coating and the alkaline tablet core. EP-A 0244380 proposes to coat cores which contain the active ingredient together with alkaline compounds or as alkaline salt with at least one layer, which is soluble in water or rapidly disintegrates in water, of nonacidic, inert pharmaceutically-acceptable substance before the enteric layer is applied.
The intermediate layer or intermediate layers act as pH-buffering zones in which hydrogen ions, which diffuse in from the outside, are able to react with the hydroxyl ions which diffuse out of the alkaline core. In order to increase the buffer capacity of the intermediate layer, it is proposed to incorporate buffer substance into the intermediate layer(s). It is possible in practice by this method to obtain rather stable compositions. However, relatively thick intermediate layers are required to prevent the unsightly discoloration which occurs even on only slight decomposition. In addition, considerable effort must be made to avoid traces of moisture during manufacture.
It is a further aim within the scope of the present invention to provide an oral pharmaceutical composition with delayed and controlled release of active ingredients in pellet or tablet form for pantoprazole, which is distinguished by great resistance to decomposition and discoloration of the active ingredient caused by moisture and other effects.
This aim is particularly advantageously achieved by providing at least one release-slowing intermediate layer of water-insoluble film former, which at the same time represents a barrier for mutual interactions between the active ingredient with an alkaline reaction and the enteric coating with an acidic reaction.
In this connection, film formers are regarded as insoluble in water when they cannot be dissolved in water without further additions (organic solvents, detergents, alkalizing substances, etc.).
The invention therefore also relates to an oral pharmaceutical composition in pellet or tablet form for acid-labile irreversible proton pump inhibitors comprising an alkaline pellet or tablet core, at least one release-slowing, release-controlling intermediate layer and an outer enteric layer which is soluble in the small intestine, wherein the intermediate layer for the pharmaceutical composition is formed from a water-insoluble film former, the film former being applied from anhydrous solution or aqueous dispersion.
The slowing of release can be achieved, for example, by a semipermeable membrane, as disclosed in numerous patents (e.g. EP B 0185331).
The details of how to achieve slowing of release are familiar to the skilled worker on the basis of his expert knowledge. The skilled worker is likewise familiar with suitable ancillary substances and vehicles for the required dosage forms (pharmaceutical formulations). Besides solvents, tablet ancillary substances and other active ingredient excipients it is possible to use, for example, tablet-coating compositions, plasticizers, antioxidants, preservatives, dyes, etc. Where incompatibilities between the active ingredients or between the active ingredients and ancillary substances are expected, suitable separating layers are provided where appropriate.
The oral pharmaceutical compositions according to the invention are distinguished from the prior art by controlled release of active ingredients and increased stability. It is particularly advantageous to keep the intermediate layer (which controls the release of active ingredients) very thin (between 20 and 80, preferably between 40 and 60, μ m), which leads to a considerable saving of material and shorter processing times. The insolubility of the intermediate layer in water means that the application of the enteric layer in the form of aqueous suspensions is not critical because there can be no dissolution of the intermediate layer. Furthermore, oral pharmaceutical compositions with a considerably smoother surface are obtained, which not only leads to a better visual appearance but also technically simplifies an imprinting process for tablets.
For a basic reaction of the pellet or tablet core it is mixed (where required increase in pH is not achieved simply by using an active-ingredient salt) with an inorganic base. Mention may be made in this connection of, for example, the pharmacologically-suitable alkali-metal, alkaline-earth-metal or earth-metal salts of weak acids and the pharmacologically-suitable hydroxides and oxides of alkaline-earth and earth metals. Sodium carbonate may be mentioned as a base to be emphasized by way of example.
Besides filler and binder, other ancillary substances, in particular lubricants and nonstick agents, and tablet disintegrants, are used in the manufacture of the tablet cores. A suitable binder is, in particular, polyvinylpyrrolidone in various degrees of polymerization. Examples of lubricants and nonstick agents which may be mentioned are higher fatty acids and their alkali-metal and alkaline-earth-metal salts, such as calcium stearate. Suitable tablet disintegrants are, in particular, chemically inert agents. Tablet disintegrants which may be mentioned as preferred are crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcelluloses and sodium starch glycolate.
Examples of film-forming polymers which can be used in the water-insoluble release-slowing intermediate layer(s) (to be applied to the pellet or tablet core) include ethylcellulose, polyvinyl acetate, Eudragit® RS, Eudragit® RL, etc. (Each of Eudragit® RS and Eudragit® RL is an ammonio methacrylate copolymer.) The release rate can be controlled not only by incorporating therein suitable water-soluble pore formers, such as PEG, lactose, mannitol, sorbitol, HPMC, etc., but also by the thickness of the coating layer applied.
The solvents or dispersants used for the release-controlling polymer dispersion are non-aqueous organic solvents, such as alcohols, ketones or halogenated hydrocarbons or mixtures of such solvents.
It is possible in a similar way to use osmotic systems with semipermeable membranes of cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, as described in U.S. Pat. No. 3,845,770, U.S. Pat. No. 3,916,899, U.S. Pat. No. 4,036,227, U.S. Pat. No. 4,093,708, U.S. Pat. No. 4,096,238, U.S. Pat. No. 4,135,514 and U.S. Pat. No. 4,142,526, to control the release of active ingredients. These can be coated with aqueous dispersions of enteric lacquers without changing release rate.
Examples of suitable polymers for the enteric coating are methacrylic acid/methyl methacrylate copolymer or methacrylic acid/ethyl methacrylate copolymer (Eudragit® L) or cellulose derivatives, such as carboxymethylethylcellulose (CMEC, Duodcel), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HP50, HPSS), hydroxypropylmethylcellulose acetate succinate (HPMCAS) or polyvinyl acetate phthalate, to which it is also possible to add, if desired, plasticizer (such as propylene glycol) and/or other additives and ancillary substances (e.g. buffers, bases, such as, preferably, aluminum hydroxide, or pigments).
The layers are applied in conventional ways using equipment customary for these purposes.
EXAMPLES
The following formulation examples explain the invention in detail without restricting it.
Example 1 Tablets I. Production of uncoated core 
______________________________________                                    
a)      Pantoprazole Na × 1.5 H2O                                   
                            45.1   mg                                     
b)      Sodium carbonate    10.0   mg                                     
c)      Mannitol            20.0   mg                                     
d)      EPMC 2910 3 cps     25.0   mg                                     
e)      HPMC 2910 15 cps    4.0    mg                                     
f)      Calcium stearate    2.1    mg                                     
                            106.2  mg                                     
______________________________________
a) is mixed with one part of b), c) and d). The remainder of b) and c) is added to the clear aqueous solution of e), and the pH is adjusted to > 10 with b). This solution is used for fluidized bed granulation. The remainder of d) and f) is added to the dried granules, and the granules are compressed in a suitable tabletting machine.
II. Release-slowing layer 
______________________________________                                    
g)       Ethylcellulose    9.85   mg                                      
h)       Lactose micronized                                               
                           2.37   mg                                      
i)       Propylene glycol  0.98   mg                                      
j)       Ammonia 25%       0.80   mg                                      
                           14.00  mg                                      
______________________________________
g) is dissolved in 165 ml of isopropanol to prepare solution (A). A fine suspension of h) in 165 ml of isopropanol is prepared using a rotor-stator agitator, and subsequently i) and j) are stirred in using a suitable agitator to prepare suspension The solution (A) and the suspension (B) are combined.
The tablet cores obtained from I are coated to an adequate layer thickness with the suspension obtained above in suitable apparatus.
III. Enteric coating 
______________________________________                                    
l)        Eudragit ® L                                                
                          13.64  mg                                       
m)        Triethyl citrate                                                
                          1.36   mg                                       
                          15.00  mg                                       
______________________________________
1) is diluted with 140 ml of water, and m) is added. The resulting dispersion is screened before processing. The dispersion from III is sprayed onto the presealed cores obtained from II in suitable equipment.
Example 2 Tablets I. Production of the uncoated core
Production of the cores took place as in Example I point I.
II. Release-slowing layer 
______________________________________                                    
g)       Polyvinyl acetate 9.15   mg                                      
h)       Lactose micronized                                               
                           2.27   mg                                      
i)       Propylene glycol  0.91   mg                                      
j)       Ammonia 25%       0.80   mg                                      
                           13.13  mg                                      
______________________________________
g) is dissolved in 150 ml of a 1:1 acetone/chloroform mixture to prepare a solution (A).
A fine dispersion of h) in 150 ml of a 1:1 acetone/choroform mixture is prepared using a rotor-stator agitator, and subsequently i) and j) are stirred in using a suitable agitator to prepare a suspension (B). Solution (A) and suspension (B) are combined.
The tablet cores obtained in I are coated to a sufficient layer thickness with the suspension obtained above in suitable apparatus.
III. Enteric coating 
______________________________________                                    
l)     Eudragit ® L     13.46   mg                                    
m)     Triethyl citrate     1.36    mg                                    
                            15.00   mg                                    
Total weight per enteric film-coated                                      
                        183.50  mg                                        
tablet                                                                    
______________________________________
1) is diluted with 135 ml of water, and m) is added. The dispersion is screened before processing.
The dispersion from III is sprayed onto the presealed cores obtained in II in suitable equipment.
Example 3 Pellets 
______________________________________                                    
I.     Starter Pellets                                                    
______________________________________                                    
a)     Sucrose pellets (0.7-0.85 mm)                                      
                             950.0  g                                     
b)     Hydroxypropylmethylcellulose                                       
                             40.0   g                                     
       2910 (USP)                                                         
c)     Propylene glycol      9.9    g                                     
d)     NaOH                  0.1    g                                     
______________________________________
a) is sprayed with an aqueous solution of b), c) and d) in a fluidized bed (Wurster method).
II. Active pellets 
______________________________________                                    
e)     Pantoprazole Na × 1.5 H                                      
                             403.0  g                                     
f)     Hydroxypropylmethylcellulose                                       
                             403.0  g                                     
       2910 (USP)                                                         
g)     Propylene glycol      201.5  g                                     
h)     NaOH                  1.0    g                                     
______________________________________
f), g), h), e) are successively dissolved in 4 liters of purified water and sprayed onto 900 g of the pellets obtained in I in a fluidized bed (Wurster method).
III. Presealed pellets
A release-slowing layer is applied in analogy to the procedure described for tablets in a pan or fluidized bed.
IV. Enteric-coated pellets
The coating is applied in analogy to the procedure described for the tablets in a pan or fluidized bed.
The pellets are subsequently packed into capsules of suitable size (e.g. size 1).
Example 4 Pellets I. Active Pellets 
______________________________________                                    
c)      Pantoprazole Na × 1.5 H.sub.2 O                             
                            403.0  g                                      
d)      Na carbonate        87.3   g                                      
e)      Microcrystalline cellulose                                        
                            117.0  g                                      
        (Avicel PH101)                                                    
f)      Na carboxymethylcellulose                                         
                            18.0   g                                      
______________________________________
c)-f) are premixed dry and subsequently moistened to a paste-like consistency with a solution of Na carbonate and Na carboxymethylcellulose in water in a conventional kneader or high-speed mixer. The resulting composition is then extruded and shaped into pellets by the extruder/rounder method familiar to the skilled worker. The moistened pellets are dried in suitable equipment (drying oven, fluidized bed, etc.).
III. Release-slowing layer
The release-slowing layer is applied in analogy to the procedure described for tablets in a pan or fluidized bed.
IV. Enteric-coated pellets
The coating is applied in analogy to the procedure described for tablets in a pan or fluidized bed.
The pellets are subsequently packed into capsules of suitable size (e.g. size 1).
The invention and its advantages are readily understood from the foregoing description. As is apparent, various changes can be made in the products and methods without departing from the spirit and scope of the invention or sacrificing its material advantages. The products and processes hereinbefore described are merely illustrative of a preferred embodiments of the invention.

Claims (15)

What is claimed is:
1. An oral pharmaceutical composition comprising pantoprazole, which is wholly or partly in slow-release form, in a multilayer tablet together with an antimicrobially-active ingredient for treating a disorder caused by Helicobacter, the multilayer tablet having a) an alkaline core with all or part of the pantoprazole and b) at least one intermediate layer which controls release of said pantoprazole.
2. An oral pharmaceutical pantoprazole composition in combination with an antimicrobially-active ingredient for treating a disorder caused by Helicobacter, wherein at least part of the pantoprazole is in slow-release form, wherein the slow-release form of pantoprazole has an alkaline pellet or tablet core, at least one intermediate layer controlling release of active ingredient, and an outer enteric layer which is soluble in the small intestine.
3. An oral pharmaceutical composition as claimed in claim 2, wherein at least one intermediate layer is formed from a water-insoluble, release-slowing film former.
4. An oral pharmaceutical composition as claimed in claim 3, wherein the film former has been applied from a solution or dispersion.
5. An oral pharmaceutical composition as claimed in claim 3, wherein the intermediate layer contains, as water-insoluble, release-slowing film former, water-insoluble cellulose ether and/or polyvinyl acetate.
6. An oral pharmaceutical composition as claimed in claim 2, wherein the outer enteric layer comprises a cellulose-based coating.
7. An oral pharmaceutical composition as claimed in claim 6, wherein the cellulose-based coating is a member selected from the group consisting of a carboxymethylethylcellulose, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxy-propylmethylcellulose phthalate and hydroxypropylmethylcellulose acetate succinate.
8. An oral pharmaceutical composition as claimed in claim 2, wherein a member selected from the group consisting of a pore former, plasticizer, buffer, base and pigment is additionally present in the intermediate layer.
9. A pharmaceutical as claimed in claim 2, wherein the antimicrobially-active ingredient is a member selected from the group consisting of bismuth subcitrate, bismuth subsalicylate, nitrofurazone, nitrofurantoin, furazolidone, metronidazole, tinidazole, nimorazole, gentamicin, neomycin, kanamycin, amikacin, streptomycin, erythromycin, azithromycin, clarithromycin, clindamycin, rifampicin, penicillin G, penicillin V, ampicillin, mezlocillin, amoxicillin, bacitracin, polymyxin, tetracyline, chlorotetracycline, oxytetracycline, minocycline, doxycycline, imipenem, loracarbef, meropenem, panipenem, cefalexin, cefoxitin, cefuroxime axetil, cefotaxime, cefpodoxime proxetil, cefaclor, cefadroxil, cephalothin, ciprofloxacin, norfloxacin, ofloxacin, pefloxacin and chloramphenicol.
10. A process for producing an oral pharmaceutical composition in pellet or tablet form for pantoprazole, as active ingredient, or for combined use thereof with an antimicrobially-active ingredient for treating a disorder caused by Helicobacter, which comprises a) incorporating the active ingredient as an alkaline salt and/or with addition of an alkaline substance in a pellet or tablet core, b) applying thereto at least one release-slowing intermediate layer comprising a water-insoluble, release-slowing film former and c) subsequently applying an outer enteric layer which is soluble in the small intestine.
11. A process as claimed in claim 10, wherein the water-insoluble, release-slowing film former for the intermediate layer is applied dissolved or dispersed in a non-aqueous organic solvent or other solvent mixture.
12. An oral pharmaceutical composition as claimed in claim 3, wherein the intermediate layer contains, as water-insoluble, release-slowing film former, ethyl cellulose, an ammonio methacrylate copolymer or polyvinyl alcohol.
13. An oral pharmaceutical composition as claimed in claim 12, wherein the outer enteric layer, which is soluble in the small intestine, comprises methacrylic acid/methyl methacrylate copolymer or methacrylic acid/ethyl methacrylate copolymer.
14. A method for treating a disorder caused by Helicobacter with pantoprazole, the improvement which comprises orally administering the pantoprazole in a composition of claim 2.
15. In a method for treating a disorder caused by Helicobacter with pantoprazole, the improvement which comprises orally administering the pantoprazole in a composition of claim 1.
US08/498,386 1995-07-05 1995-07-05 Oral pharmaceutical composition with delayed release of active ingredient for pantoprazole Expired - Lifetime US5945124A (en)

Priority Applications (23)

Application Number Priority Date Filing Date Title
US08/498,386 US5945124A (en) 1995-07-05 1995-07-05 Oral pharmaceutical composition with delayed release of active ingredient for pantoprazole
PCT/EP1996/002892 WO1997002020A1 (en) 1995-07-05 1996-07-02 Oral pharmaceutical composition containing antimicrobial actives and sustained release pantoprazole
AT02005081T ATE324872T1 (en) 1995-07-05 1996-07-02 ORAL PHARMACEUTICAL COMPOSITION WITH DELAYED RELEASE PROTON PUMP INHIBITORS
AT96924849T ATE232090T1 (en) 1995-07-05 1996-07-02 ORAL PHARMACEUTICAL COMPOSITIONS CONTAINING SUSTAINED RELEASE PANTOPRAZOLE AND ANTIMICROBIAL AGENTS
DE69636104T DE69636104T2 (en) 1995-07-05 1996-07-02 Oral pharmaceutical composition with sustained-release of proton pump inhibitors
EP02005081A EP1213015B1 (en) 1995-07-05 1996-07-02 Oral pharmaceutical composition with delayed release of proton pump inhibitors
CA002232450A CA2232450C (en) 1995-07-05 1996-07-02 Oral pharmaceutical composition containing antimicrobial actives and sustained release pantoprazole
DE69626116T DE69626116T2 (en) 1995-07-05 1996-07-02 ORAL PHARMACEUTICAL COMPOSITIONS CONTAINING PANTOPRAZOL WITH DELAYED RELEASE AND ANTIMICROBIAL AGENTS
ES02005081T ES2263700T3 (en) 1995-07-05 1996-07-02 ORAL PHARMACEUTICAL COMPOSITION WITH DELAYED RELEASE OF INHIBITORS OF THE PUMPS OF PROTONS.
HK98112159.5A HK1010836B (en) 1995-07-05 1996-07-02 Oral pharmaceutical composition containing antimicrobial actives and sustained release pantoprazole
SI9630595T SI0841903T1 (en) 1995-07-05 1996-07-02 Oral pharmaceutical composition containing antimicrobial actives and sustained release pantoprazole
PT96924849T PT841903E (en) 1995-07-05 1996-07-02 ORAL PHARMACEUTICAL COMPOSITION CONTAINING ACTIVE ANTIMICROBIAL AGENTS AND PANTOPRAZOLE WITH DEFERRED LIBERATION
DK02005081T DK1213015T3 (en) 1995-07-05 1996-07-02 Oral pharmaceutical composition with delayed release of proton pump inhibitors
ES96924849T ES2192226T3 (en) 1995-07-05 1996-07-02 ORAL PHARMACEUTICAL COMPOSITION CONTAINING ANTIMICROBIAL ACTIVE AGENTS AND PROLONGED LIBERATION PANTOPRAZOL.
AU65174/96A AU6517496A (en) 1995-07-05 1996-07-02 Oral pharmaceutical composition containing antimicrobial actives and sustained release pantoprazole
JP9504811A JPH11508577A (en) 1995-07-05 1996-07-02 Oral drug containing antibacterial active substance and sustained release pantoprazole
CA002587000A CA2587000A1 (en) 1995-07-05 1996-07-02 Oral pharmaceutical composition containing antimicrobial actives and sustained release pantoprazole
EP96924849A EP0841903B1 (en) 1995-07-05 1996-07-02 Oral pharmaceutical composition containing antimicrobial actives and sustained release pantoprazole
DK96924849T DK0841903T3 (en) 1995-07-05 1996-07-02 Oral pharmaceutical preparations containing antimicrobially active active substances and sustained release pantoprazole
PT02005081T PT1213015E (en) 1995-07-05 1996-07-02 ORAL PHARMACEUTICAL COMPOSITION WITH DELAYED RELEASE OF INHIBITORS FROM THE PUMP PUMP
US09/042,090 US6068856A (en) 1995-07-05 1998-03-13 Oral pharmaceutical composition with delayed release of active ingredient for pantoprazole
US09/461,388 US6274173B1 (en) 1995-07-05 1999-12-15 Oral pharmaceutical composition with delayed release of active ingredient for pantoprazole
CY0400047A CY2459B1 (en) 1995-07-05 2004-06-11 Oral pharmaceutical composition containing antimicrobial actives and sustained release pantoprazole.

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US09/042,090 Expired - Lifetime US6068856A (en) 1995-07-05 1998-03-13 Oral pharmaceutical composition with delayed release of active ingredient for pantoprazole
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US (3) US5945124A (en)
EP (2) EP1213015B1 (en)
JP (1) JPH11508577A (en)
AT (2) ATE232090T1 (en)
AU (1) AU6517496A (en)
CA (2) CA2587000A1 (en)
CY (1) CY2459B1 (en)
DE (2) DE69626116T2 (en)
DK (2) DK0841903T3 (en)
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US6362169B1 (en) * 1998-02-24 2002-03-26 Kaneka Corporation Antibacterial compositions with synergistic effect, drugs and remedies for digestive diseases containing the same, process for the production thereof and preparations associated therewith
US6605303B1 (en) * 1997-12-22 2003-08-12 Astrazeneca Ab Oral pharmaceutical extended release dosage form
US6610323B1 (en) 1997-12-22 2003-08-26 Astrazeneca Ab Oral pharmaceutical pulsed release dosage form
US20030211147A1 (en) * 2000-09-29 2003-11-13 Cullen Daniel J. Proton pump inhibitor formulation
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US20040101558A1 (en) * 2000-12-07 2004-05-27 Rango Dietrich Pharmaceutical preparation in the form of a paste comprising an acid-labile active ingredient
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US6068856A (en) 2000-05-30
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CA2232450A1 (en) 1997-01-23
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AU6517496A (en) 1997-02-05
DK1213015T3 (en) 2006-08-14
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US6274173B1 (en) 2001-08-14
PT841903E (en) 2003-06-30

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